ANVISA – The Brazilian Health Surveillance Agency

The implementation of the Common Technical Document (CTD) format facilitating the submission and review process for the countries that adopted the format established by the International Conference on Harmonization (ICH) is very common; however, for the countries that are new and have not adopted the CTD format, some changes are required from a CTD to the specific countries’ regulations.

In the case of the Brazilian registration, there are regional specificities and similarities with the CTD format applicable in the ICH countries members. The Brazilian regulation shows that the dossier is structured for product registration in two main parts:

1.Administrative: Compilation of all administrative data, including specific requirements for imported products.

2.Technical: Technical reports, including quality, nonclinical, and clinical information, presenting similarities to the CTD Modules 2, 3, 4, and 5.

Clinical trial in brazil

Procedure and approval procedure of Clinical trials for the pharmaceutical industry in Brazil as follow.

Institutions involved in the approval process

In Brazil, three different institutions:

CONEP (Central)  Comissão Nacional de Ética em Pesquisa,

CEP (local committee) Comitê de Ética em Pesquisa , and

ANVISA (Agência Nacional de Vigilância Sanitária),

are responsible for reviewing and approving regulatory documents to initiate a clinical study in this region. The CONEP and ANVISA processes happen in parallel.

1.  CONEP, translated from Portuguese as National Committee of Ethics in Research: this committee is the Central Ethics Committee, which is related to the Ministry of Health, is responsible for review and approval of the ethical aspects of a clinical trial in Brazil.

a.The Coordinating CEP is responsible for submission of the clinical trial to the CONEP, and will directly work with the CONEP regarding the study assessment. A written letter will be issued if the CONEP approves the study.

b.Otherwise, CONEP will communicate questions to the Coordinating site through the Coordinating CEP.

Questions are raised in one of three options:

• Questions were raised:

This is the case that the Coordinating CEP receives a set of questions from CONEP and forwards to the Coordinating Site and the Sponsor. The Sponsor will prepare the responses and comments on a question-by-question basis and send back to the Coordinating Site.

• Questions are raised under “approval with the recommendation”:

In this case, the clinical team must provide CONEP recommendations, along with all necessary updated documents to all sites for submission to the CEPS. All CEPs must review and approve the changes before the study starts at the respective sites.

• Questions are raised under “Pending” status:

In this case, the clinical team must provide the recommendations, along with all necessary updated documents to the Coordinating Site only, for submission to the Coordinating CEP. After approval, the coordinating CEP submits the responses to CONEP for review. After CONEP approval of the study, all remaining sites and the respective CEPS must receive the updated approved documents for review and local approval before the study starts at each site.

2. CEP, translated from Portuguese as Committee of Ethics in Research: these are local ethics committees that are registered with CONEP (the central committee). They can review and approve clinical trials conducted at an institution.

a.Each company should have a list of documents and information required for the clinical trial.

b.These documents and information are received from the sponsor and the study sites. These documents may contain templates of forms, documents, and statements required for the study. They also include statements related to general study information. For the first three study sites, one of these sites is selected as Coordinating Site; then its CEP is designated as the Coordinating CEP. All documentation must be provided in Portuguese; any translated document must be accompanied by the corresponding certificate of translation.

3. ANVISA: this is the Brazilian Regulatory Agency. This group is responsible for reviewing all technical aspects and issuing the Import License for a clinical trial. Two types of dossiers are reviewed by ANVISA:

a.Processo de Anuência (Consent Process): the main application dossier for initial submission. This dossier will receive a unique specific number from ANVISA to be used for all updates.

b.Processo de Inclusão de Centros (Inclusion Centers Process): the dossier for adding sites when every site other than the one submitted in the Processo de Anuência. This document will carry the same number as the one previously assigned.

Documentation required

ANVISA prefers to have all information submitted entirely in the dossiers. However, it is acceptable to submit the dossier with part of the information pending and then update the remaining documents as they are available. Responses will be made to address each question that ANVISA raises.

Several documents submitted are briefly described below:

a.Brazilian Informed Consent Form (ICF) template that must be translated into Portuguese and adapted to the local government. There are three different types of ICF that one may find:

• Master ICF is the primary document that is submitted
• Revised ICF is done whenever the changes affect any local requirement.
• Revisions to site-specific ICF is any revision to a site-specific ICF.

b. Importation which includes documents related to Import License request. This document consists of any updates to the list of materials to be imported. It consists of all study drug documentation (such as Certificate of Analysis, BSE Certificates, and documents). This request is valid during one year of the clinical trial and multiple shipments. If the length of the clinical trial or quantities needed exceeds the approved terms, then an extension to cover the extra needs must be done.

c.All master labels for study drugs and materials to ensure they contain all the expected information. These labels are in the English language, and also in its translation to Portuguese.

d.Any advertisement or announcement for the study that will be distributed to the sites.

e.Data protection requirements to be met in the confidentiality and data handling section of the ICF.

f. Insurance and Indemnity assessed as the Sponsor must provide a Medical Assistance Letter for injuries related to the study.

g. Amendments included in the protocol. These amendments needed to be approved by each CEP before the implementation and notified to ANVISA. CONEP approval is not mandatory but can be requested.

h. Safety report must be done according to local requirements. This document is received from the Sponsor in both English and Portuguese.

i. Progress and annual reports are prepared and submitted following local requirements. The study staff must submit an interim report to its CEP every six months.

j. End-of-trial notification is similar to the Progress and Annual Reports at sites and with ANVISA.

k. Clinical trial reports are prepared and submitted to ANVISA only as required by the Sponsor.

Approval process

The regulatory approval process typically passes through 2 ethical evaluations: the institutional CEP and CONEP. The Coordinating Ethics Committee (EC) submits the multicenter research center research protocol for CONEP for review, and approval would apply to all sites.

CONEP submission requires

• the protocol,
• the ICF, investigator’s brochure,
• Power of Attorney,
• the protocol approved a letter from Coordinating EC, and
• all other documents submitted to the Coordinating EC.

Bioavailability / Bioequivalence Centers